Tumor suppressors function as a bottleneck against cellular reprogramming into iPS cells

Abstract

AbstractGenerating individual specific pluoripotent stem cells from differentiated cells is essential for regenerative medicine. Here, I propose that the tumor suppressor TA-p73/p63-dependent microRNA network may inhibit self-renewal and reprogramming. It has recently been shown that C-terminal NHL domain of TRIM32, an ubiquitin ligase, binds to Argonaute 1(Ago-1, a component of RNA information silencing complex) and thereby the complex TRIM32-Ago1 promotes the efficiency of processing of microRNA-134. Bioinformatics analysis of TRIM32 promoter revealed five p73/p63 binding sites in the TRIM32 promoter, indicating that it could be a transcriptional target of TA-p73/p63. This data suggests a possibility that the TA-p73/p63, by increasing the expression of TRIM32, it could increase the Ago1/2 activity and thereby it could increase the processing of miR-134. Further, bioinformatics analysis of miR-134 suggests that it could inhibit the expression of Nanog, Sox-2, Oct4, and LRH-1. This data suggests that TA-p73/p63 could down regulate reprogramming factors Nanog, Sox-2, Oct-4, and LRH-1 through its target miR-134. Furthermore, p53/TA-p73/p63 may increase the expression of let-7, which, in turn, inhibits lin-28 expression to inhibit reprogramming. Therefore, inhibiting the expression of TA-p73/p63 will be useful in improving reprogramming efficiency. Analysis of microarray data with bioinformatics and computational biology approach revealed that p53/TA-p73/p63-microRNAs could disrupt the core-reprogramming network in ES cells and thereby they could inhibit self-renewal and reprogramming. Remarkably, miR-106 appears to increase the expression of TA-p73 by suppressing its negative regulator, Itch, indicating that by inhibiting the expression of TA-p73/p63 through anti-miR-106, one could increase the efficiency of reprogramming. This study will present molecular insights into why eliminating tumor suppressor function is indispensable for improving reprogramming efficiency.